Alzheimer's disease (AD), the most common cause of dementia, is estimated to affect 5% of those over 65 years of age and 40% of those over 80 years of age, or a total of approximately 20 million people worldwide. The neuropathological characteristics of AD include: .beta.-amyloid plaques that are diagnostic when associated with dystrophic neurites; neurofibrillary tangles; loss of neurons and synapses; and proliferation of glial cells. The last few years have seen substantial progress in unravelling the genetic influences in AD. A small proportion of AD cases are inherited as an autosomal dominant trait and are attributable to point mutations in genes encoding .beta.-amyloid precursor protein (.beta.APP),.sup.1 presenilin 1,.sup.2 or presenilin 2..sup.3 A major genetic risk factor for the much more common sporadic AD is possession of the apolipoprotein E (APOE) e4 allele..sup.4 However possession of APOE e4 is neither necessary nor sufficient for the development of AD, leaving scope for other potential genetic or environmental influences.
Interleukin-1 (IL-1) is a potent pro-inflammatory cytokine that is markedly overexpressed in Alzheimer brain, predominantly in microglia,.sup.5 suggesting a role for inflammatory processes in AD pathogenesis..sup.6 This idea has received support from epidemiological studies showing that use of anti-inflammatory agents, in particular non-steroidal anti-inflammatory drugs, is associated with delayed onset or slowed progression of disease..sup.7 IL-1 has two structurally distinct forms, IL-1a and IL-1.beta., encoded by separate genes (IL-1 and IL-1B, respectively) located in a cluster on the long arm of chromosome 2 that also includes the IL-1 receptor antagonist gene..sup.8 Common polymorphisms have been described in both genes and there is evidence that they have functional significance. A polymorphism of the IL-1B gene (+3953), for instance, introduces a Taq1 restriction site resulting in two alleles, designated allele 1 and allele 2..sup.9 Homozygosity for allele 2 of IL-1B is associated with a fourfold increase in production of IL-1.beta. compared to homozygosity for allele 1..sup.9 A polymorphism in the 5' regulatory region of the IL-1 gene (a C to T transition at position -889 relative to the start site of transcription) again results in two alleles, also designated allele 1 and allele 2..sup.10 Both of these IL-1 polymorphisms have been associated with inflammatory diseases. For instance, IL-1 allele 2 has been associated with juvenile rheumatoid arthritis..sup.10
Genetic testing is now possible (see U.S. Pat. Nos. 4,582,788, 5,110,920 and 5,686,246) for diseases associated with or caused by one to two genes, once the genes are identified, to determine the risk of a person carrying a given gene for the disease (see for example U.S. Pat. Nos. 4,801,531, 4,666,828, 5,268,267 and 5,686,246). These patents are hereby incorporated by reference into this disclosure.
Many altered physiological functions induce or are caused by inflammatory and other immune mechanisms (see U.S. Pat. No. 5,328,829, column 1, for a review). Due to the commonality of the immune response in almost all disease states, research on inflammatory markers as genetic markers has had very limited success at differentiating predisposition to diseases. U.S. Pat. No. 5,686,246, is a notable exception, in that the inventors correlated IL-1a and IL-1b mutations with the susceptibility to severe periodontal disease.
Association of a single cytokine polymorphism and disease states have been found as, for example, in Systemic Lupus Erythematosus, Ulcerative Colitis and Juvenile rheumatoid arthritis (Mansfield et al., 1994; Verjans et al., 1992; Blakemore et al., 1994; McGuire et al., 1994; McDowell et al., 1995).
Therefore, it was an objective of the present invention to determine if genetic factors that are associated with inflammatory and other immune responses correlate with Alzheimer's disease. If so, it would be useful to identify the genetic factors and thereby identify persons who are susceptible to Alzheimer's disease for the purpose of providing prophylactic treatment.